Hyperaldosteronism, caused by an aldosterone-producing

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1 CONTROVERSIES IN HYPERTENSION Adrenal Vein Sampling Is the Preferred Method to Select Patients With Primary Aldosteronism for Adrenalectomy Pro Side of the Argument Gian Paolo Rossi, John W. Funder Hyperaldosteronism, caused by an aldosterone-producing adenoma (APA) or much less commonly unilateral adrenal hyperplasia, can be cured or improved in >95% of patients by unilateral laparoscopic adrenalectomy. Approximately 50% of these patients have a complete clinical remission, with blood pressure returning to normal levels without the need for antihypertensives. In the remaining 50%, blood pressure levels commonly fall but not into the normal range, despite biochemical cure: such patients require continuing but usually lower levels of antihypertensive therapy. The persistent hypertension is commonly attributed to vascular damage or underlying primary hypertension. APA/unilateral adrenal hyperplasia together account for 5% of hypertension, 1 with the remainder of primary aldosteronism (PA) caused by bilateral adrenal hyperplasia. The prevalence of bilateral adrenal hyperplasia, commonly a less florid form of PA, seems currently to reflect the disparate cutoffs used. Reported levels are equal to or less than those of unilateral disease if strict cutoffs in screening and confirmatory testing are used, and approximately double when more relaxed cutoffs are in place. Such patients are not treated by adrenalectomy, except in a handful of cases of fulminant familial hypertension type III, but with mineralocorticoid receptor antagonists, amiloride, and other antihypertensive agents as required. A large, recent study has shown that a markedly elevated aldosterone-to-renin ratio accurately identified patients with an APA but not its location. 2 In most jurisdictions, the advantages of laparoscopic adrenalectomy for unilateral disease are well recognized. These include total cure in half the patients lateralized who are relieved of the burden and cost of lifetime medication and lower levels of medication for blood pressure in the remainder. In addition, patients note a marked improvement in well-being and quality of life. For this reason, adrenal venous sampling (AVS) is recommended 3,4 for confirmed PA patients, with some exceptions. Rarely are patients unfit for laparoscopic surgery: in most (but not all) countries patients opt for surgery, when the advantages are clearly explained in consenting. Finally, but not formally evidence-based, at the discretion of the managing physician, the patient may be referred for surgery on the basis of age (<35 years), PAC >20 ng/dl, totally suppressed plasma renin, plus a unilateral adenoma and a normal contralateral gland on imaging. Imaging by computed tomography (CT) is recommended for all patients confirmed to have PA, to exclude the rare cases of adrenal carcinoma, and to assist in catheter placement. There have been a series of studies, from the United States, Europe, and Australia, attempting to match what seems to be a potential unilateral source of hyperaldosteronism by imaging with definitive lateralization by AVS, confirmed post-operatively. In reviewing the initial Brisbane experience, Gordon 5 reported that in patients with proven APA, CT contributed to lateralization in only just over half (59/111) and in <25% of APAs <1 cm in diameter. A follow-up study from the same group was done by Stowasser et al. 6 This study is important for 2 reasons. First, it showed that with rigorous screening and confirmatory testing of all nonselected hypertensives, the prevalence of PA was unexpectedly high with only a minority of patients so identified being hypokalemic (13%). Second, aldosterone The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Clinica dell Ipertensione Arteriosa (G.P.R.) and Department of Medicine, DIMED (G.P.R.), University of Padova, Italy; Hudson Institute of Medical Research, Clayton Victoria, Australia (J.W.F.); and Monash University, Clayton, Victoria, Australia (J.W.F.). Correspondence to Gian Paolo Rossi, Department of Medicine, DIMED Internal Medicine 4, University Hospital, Via Giustiniani, 2, Padova, Italy. gianpaolo.rossi@unipd.it (Hypertension. 2018;71:5-9. DOI: /HYPERTENSIONAHA ) 2017 American Heart Association, Inc. Hypertension is available at DOI: /HYPERTENSIONAHA

2 6 Hypertension January 2018 overproduction was lateralized to 1 adrenal in 15 patients (6 hypokalemic) and was bilateral in 34, of whom none were hypokalemic. Of the 15 patients who lateralized, CT showed an ipsilateral mass in 6 and a contralateral mass in 1. In an early study from the Mayo Clinic of 203 patients who were evaluated by both CT and AVS, 7 CT was accurate in only 53% of patients: on the basis of CT alone, 42 (22%) of patients would have been inappropriately excluded from the surgery, and 48 (25%) undergone unnecessary or inappropriate surgery. In a subsequent study from Dallas 8 on 41 patients with PA, concordance between CT and AVS was similarly just over half (54%). Similar findings characterize a meta-analysis from Nijmegen, 9 on a total of 950 patients, some of whom lacked appropriate follow-up data. In 359 of the 950 patients (37.8%) CT/magnetic resonance imaging (MRI) results did not agree with those of AVS. Had imaging been the sole guide, inappropriate exclusion from adrenalectomy would have occurred in 19.1% of patients, inappropriate adrenalectomy in 14.6%, and adrenalectomy on the wrong side in 3.9%. The authors conclusion was that relying only on CT/MRI may lead to inappropriate treatment of patients with PA, a model of academic understatement for an error rate of almost 2 in 5 patients. In a second study from the Mayo clinic spanning 19 years, again, similar results were found. 10 Of 143 patients who underwent unilateral adrenalectomy and were followed up long term, AVS identified the surgically documented side in 97% of patients, and adrenal imaging in 59%, again a difference of 38%. An interesting corollary of the study was that imaging and AVS were concordant in patients <35 years of age, but there were only 6 such patients. Finally, in a recent study from Munich, 11 on 175 patients who underwent unilateral laparoscopic adrenalectomy for PA after CT/MRI and lateralization by AVS, CT imaging produced 39% discordant results, and MRI 41%: the conclusion proffered by the authors was the accuracy of CT and MRI in predicting unilateral disease is poor. AVS appears to be an essential diagnostic step to identify those patients who may benefit from adrenalectomy. Academic understatement seems de rigueur: may in Nijmegen, appears in Munich. This evidence, and the consensus over time and across continents, represent the base for which venous sampling is recommended in all but rare circumstances. Recently, these data have been challenged by the authors of the SPARTACUS trial (Subtyping Primary Aldosteronism: a Randomized Trial Comparing Adrenal Vein Sampling and Computed Tomography Scan), a randomized prospective study on 184 patients in Holland and Poland. 12 After imaging, the subjects were divided into 2 groups: 92 patients underwent AVS with cosyntropin and were referred for unilateral adrenalectomy (or not) on the basis of demonstrated unilateral hyperaldosteronism: the other 92 patients underwent unilateral adrenalectomy (or not) on the basis of CT imaging. In each group, exactly half the patients were adjudged to have a unilateral source of hyperaldosteronism, so that a neat series of 4 groups of 46 patients were able to be compared. The reported results were as follows. A minority of patients in both arms reached target blood pressure (AVS 41/92:45%; CT 39/92:42%), despite intensive medication measures as daily defined doses (3.0 in both arms), and in median number of drugs (2 in both). No differences were found in terms of quality of life on Rand-36 physical and mental scores. Of the patients undergoing adrenalectomy in each arm, 9 of those on the basis of CT remained hyperaldosteronemic and 5 in the AVS group. The AVS group showed a nonsignificant mean difference in quality-adjusted lifeyears and was significantly more expensive than CT alone. There were no differences in adverse events (CT 159, 9 serious; AVS 187, 12 serious). The authors interpret their data as showing that treatment of PA based on CT or AVS did not show significant differences in intensity of antihypertensive medication or clinical benefits for patients after 1-year follow-up. This finding challenges the current recommendation to perform AVS in all patients with PA. It should be noted that the current guideline does not recommend AVS for all AVS patients, as stated above. Even were these exclusions factored in, whether or not the authors finding challenges the current recommendations depends entirely on 2 things the evidence that the present study offers and the extent to which it can be generalized across the spectrum of PA. In terms of the evidence base, there are many issues that make it less convincing. In a study 13 including patients from Nijmegen over the same period, 2010 to 2013, on sequential patients presenting with AVS-confirmed PA and followed for at least 6 months, hyperaldosteronism cure (normalization of ARR and [K + ]) was achieved in 37 out of 38 patients, with a failure rate of 2.6%; in the present study, a 4-fold higher failure rate was reported. There are no convincing data on APA localizing more in one adrenal than the other: consistent with this is the finding on AVS of right-sided APA in 22 patients and 26 on the left. In a curious disparity, on CT, the authors reported right-sided enlargement in 12 patients and left-sided enlargement in 39. Differing central and local CT findings were reported in 14 patients, with consensus reached in 3, 1 case of adrenalectomy on the local CT diagnosis, and in 10 cases relegation to mineralocorticoid antagonist therapy. The failure of over half the patients in each treatment group to attain goal blood pressure does not inspire confidence in the unusual treatment regime used spironolactone starting at 25 mg/d, up to 200 mg/d as inexplicably divided doses (or equivalent doses of eplerenone if spironolactone was poorly tolerated), and then additional antihypertensives, to a median of 2.0 drugs post-operatively in all groups. Taken together, this combination of anomalies dictates a measure of caution in their use to challenge the consistent findings of clear superiority of AVS over CT to identify lateralized hyperaldosteronism. If caution is required in terms of the evidence base derived from the particular patients enrolled in the study, it is doubly necessary when the authors attempt to generalize from their cohort to PA across the board. To begin with, the patients are very much not representative of the wider population of PA patients. First, there is a major problem of discrepancy in patient sex: of the 184 subjects, 134 are male and only 50 female. This is not the fault of the authors, in that it reflects referral patterns in both Nijmegen and Warsaw, as also shown in their cohorts in the study previously cited (Nijmegen 9/38 female, Warsaw 8/30 female) 13 ; such gross sex disparities are not seen in many other jurisdictions. 13 Second, the mean

3 Rossi and Funder AVS, CT, and Lateralization of APA 7 age of the patients studied was 53.1 years, again considerably higher than the norm elsewhere. Third, the entry criteria (hyperkalemia and resistant hypertension) are very much skewed to the florid end of PA, consistent with the remarkably low rates of attaining normotension, which ranged from 41% to 46% (including those clinically cured by adrenalectomy). Fourth, AVS was done under cosyntropin, which may preclude generalization to AVS without stimulation. Fifth, the medication schedule is not one in common use, in terms either of the escalating spironolactone/eplerenone dosing, or the use of daily defined dose in the context of a major therapeutic deficiency in attaining normotension. Finally, the large number of adverse events 340 in 136 patients, 21 serious may reflect sex, age, florid disease, or the unusual medication regimen but underscores the perils of generalization to less selected patient populations with hyperaldosteronism. In summary, when a study shows no differences between groups or procedures, it is incumbent on those responsible to weigh up possible factors that may obscure difference and to recognize the limitations in attempting to generalize from their results. In the abstract of his recent invited presentation at the Endocrine Society meetings in Orlando (April 2017) Jaap Deinum characterized AVS as the gold standard. The gold standard was a financial instrument against which diverse currencies around the globe could be fixed (4 US dollars to 1 pound sterling, for example), which clearly outlived its validity and was dispensed with almost a century ago. Like the gold standard, adrenal vein sampling is not perfect: despite these imperfections, to be categorized below, it retains its validity as a measure over imaging alone. What might be challenged over the next 5 years is its continuing use for essentially all patients with proven PA that is, an amplification of the categories of proceeding to surgery without AVS and conversely proceeding to medical therapy, similarly without AVS. First of all, the current difficulties. In essence, the problem is that AVS has developed over the past 3 decades essentially as a cottage industry. A series of grandmothers in a country town may all make good apple pies for the local church fair all tasty but all in some way different. AVS is somehow similar, and just as individual grandmothers are sometimes not on speaking terms, differences of opinion are not unknown in our cottage industry. The variations in methodology, cutoffs, indices, assay methods, comparators, and interpretation are legion. First up, AVS needs a dedicated, experienced, highthroughput interventionist for success: this is widely agreed, but on occasion not the case, leading to unacceptable levels of failure and complication. 14 The right side is often more difficult to access than the left; again widely agreed and leading to the development of side-specific cannulae. Several centers have developed microcannulation techniques to localize the source of the hyperaldosteronism within the adrenal 15 : notwithstanding its elegance, whether or not this is usefully generalized remains moot. And then, the real differences emerge. Is AVS sequential or simultaneous? Half the world eschews using cosyntropin; those groups that use it vary in terms of timing, dose, and bolus versus constant infusion. Indices of lateralization and selectivity vary; cortisol as the denominator is in common use to gauge aldosterone excess as the numerator, but metanephrine or androstenedione may be better. 16 Intraprocedural steroid measurement may refine diagnosis and reduce the necessity for second-round AVS, but is yet not widely available, and needs to be validated in a randomized clinical trial, as recently previewed. 17 It is tempting to say ad infinitum, whereas if there are a dozen variations, it is only factorial 12 not infinity but a large number. The wonder of it all is that despite all this variation, it works and it does. There may be factorial 12 variations across the grandmothers apple pies, but they all usually taste much better than their store-bought, mass-produced equivalent. It should be noted that AVS is not the only cottage industry aspect of the management of PA we have wide variations in cutoffs for screening and for a positive confirmatory test the latter by any one (or more) of half a dozen different methods. Nobody wants the management of PA to become a mechanical exercise; management of individual patients ultimately rests with the physician involved. What we do need is harmonization in terms of assay methodology, cutoffs, and confirmatory/exclusion testing, all of which will require a degree of unwonted change and collegiality to succeed. The other, important thing we need is to be able to sort patients with PA into 3 groups as follows: those with a high probability of unilateral disease, a gray zone of those who need AVS for lateralization, and those with a low probability. The context is crucial to this exercise. As SPARTACUS noted, AVS is relatively expensive: if we are to have robust sorting mechanisms, they need to be cheap. There is growing evidence for hyperaldosteronism, inappropriate for sodium status, in an increasing percentage of hypertensives, reflecting at least in part our current discounting of the role of adrenocorticotrophic hormone in aldosterone secretion. The same seems to be true in normotensives, with normal aldosterone-to-renin ratios on the basis of conventional spot plasma aldosterone measurement, but with clearly elevated 24-hour urinary aldosterone. 22 Hypertensive or normotensive, such patients are at risk of increased cardiovascular damage, as demonstrated for young, normotensive patients with familial hyperaldosteronism type Such patients thus need treatment, and the prospect of a vastly expanded pool of PA patients puts alternatives to universal AVS front and center. Given the current level of primary care practitioner knowledge of PA, 24 there is, however, a reasonable time frame in which to seek and validate additional strategies. These range from peripheral levels of 18 oxo-cortisol, which in retrospective studies is highest in established unilateral disease with a gray area group and a group with levels clearly lower than those in unilateral disease 25 ; if and when this is confirmed and extended, it would suggest that AVS might be avoided in the third group. One caveat is that hybrid steroid levels are not different in the 20% of APA patients with the angiotensin-responsive subtype from those in bilateral adrenal hyperplasia. 26 Ideally, then, prior angiotensin infusion might confine AVS to this subtype, a signal advance. Patients who seem to have bilateral adrenal hyperplasia are the group that may well expand with a higher prevalence of PA and would be treated with low-dose mineralocorticoid receptor antagonist plus antihypertensives if and as required. Similar distinction not necessarily into tertiles may well

4 8 Hypertension January 2018 be enhanced by a multisteroid fingerprint characteristic of an aldosterone-producing adenoma. 27 Given that well over half of such APA carry a somatic mutation, efforts similarly are being made to identify such cells released into the circulation; if successful, such a marker would confer a high index of correct lateralization of solitary nodules, particularly in younger patients. In some jurisdictions, CT-guided injection of alcohol into suspect adenomas has been tried as a relatively inexpensive alternative to unilateral adrenalectomy solely on the basis of imaging. The aim of all such efforts is not to dispense with AVS but to extend the level of near certainty in those patients who on a credible basis are unlikely to have unilateral disease. With the advent of better recognition of the prevalence of PA, the patient load is likely to much grow and for the capacity for near-universal AVS to be unbearably strained; until that time, it remains the only reliable way to lateralize hyperaldosteronism. It is our sincere hope that there will be cheap, proven, and reliable methods as adjuvants to AVS in parsing the PA population. Whatever the outcome, it is clear that in the overwhelming majority of cases of PA, this will not be simple reliance on imaging, which has been consistently proven to misidentify 40% of APA patients, with totally unacceptable consequences. The SPARTACUS trial is open to criticism on a variety of fronts and is a unsound basis in terms of generalization: our case rests. Sources of Funding This study was supported by the COST BM1301 Aldosterone and Mineralocorticoid Receptor (ADMIRE) EU program (to G.P. Rossi) and by FORICA (The Foundation for Advanced Research in Hypertension and Cardiovascular Disease) to G.P. Rossi. This Work is supported by the Victorian Government s Operational Infrastructure Support Program to J.W. Funder. None. Disclosures References 1. Rossi GP, Bernini G, Caliumi C, et al; PAPY Study Investigators. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol. 2006;48: doi: /j. jacc Maiolino G, Rossitto G, Bisogni V, Cesari M, Seccia TM,Plebani M, Rossi GP; PAPY Investigators. Quantitative value of aldosterone-renin ratio for detection of aldosterone-producing adenoma: the aldosteronerenin ratio for primary aldosteronism (AQUARR) study. J Am Heart Assoc. 2017;6:e doi: /JAHA Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, Stowasser M, Young WF Jr. The management of primary aldosteronism: case detection, diagnosis, and treatment: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016;101: doi: /jc Nishikawa T, Omura M, Satoh F, Shibata H, Takahashi K, Tamura N, Tanabe A; Task Force Committee on Primary Aldosteronism, The Japan Endocrine Society. Guidelines for the diagnosis and treatment of primary aldosteronism the Japan Endocrine Society Endocr J. 2011;58: doi: /endocrj.EJ Gordon RD. Diagnostic investigations in primary aldosteronism. In: Zanchetti A, ed. Clinical Medicine Series on Hypertension. London, United Kingdom: McGraw Hill; Stowasser M, Gordon RD, Gunasekera TG, Cowley DC, Ward G, Archibald C, Smithers BM. High rate of detection of primary aldosteronism, including surgically treatable forms, after non-selective screening of hypertensive patients. J Hypertens. 2003;21: doi: /01. hjh Young WF, Stanson AW, Thompson GB, Grant CS, Farley DR, van Heerden JA. Role for adrenal venous sampling in primary aldosteronism. Surgery. 2004;136: doi: /j.surg Nwariaku FE, Miller BS, Auchus R, Holt S, Watumull L, Dolmatch B, Nesbitt S, Vongpatanasin W, Victor R, Wians F, Livingston E, Snyder WH III. Primary hyperaldosteronism: effect of adrenal vein sampling on surgical outcome. Arch Surg. 2006;141: ; discussion 502. doi: / archsurg Kempers MJ, Lenders JW, van Outheusden L, van der Wilt GJ, Schultze Kool LJ, Hermus AR, Deinum J. Systematic review: diagnostic procedures to differentiate unilateral from bilateral adrenal abnormality in primary aldosteronism. Ann Intern Med. 2009;151: Lim V, Guo Q, Grant CS, Thompson GB, Richards ML, Farley DR, Young WF Jr. Accuracy of adrenal imaging and adrenal venous sampling in predicting surgical cure of primary aldosteronism. J Clin Endocrinol Metab. 2014;99: doi: /jc Ladurner R, Sommerey S, Buechner S, Dietz A, Degenhart C, Hallfeldt K, Gallwas J. Accuracy of adrenal imaging and adrenal venous sampling in diagnosing unilateral primary aldosteronism. Eur J Clin Invest. 2017;47: doi: /eci Dekkers T, Prejbisz A, Kool LJ, et al; SPARTACUS Investigators. Adrenal vein sampling versus CT scan to determine treatment in primary aldosteronism: an outcome-based randomised diagnostic trial. Lancet Diabetes Endocrinol. 2016;4: doi: /S (16) Williams TA, Lenders J, Mulatero P, et al. Outcomes after adrenalectomy for unilateral primary aldosteronism: an international consensus on outcome measures and analysis of remission rates in an international cohort. Lancet Diabetes Endocrinol. 2017;5: doi: / S (17) Rossi GP, Auchus RJ, Brown M, Lenders JW, Naruse M, Plouin PF, Satoh F, Young WF Jr. An expert consensus statement on use of adrenal vein sampling for the subtyping of primary aldosteronism. Hypertension. 2014;63: doi: /HYPERTENSIONAHA Satoh F, Morimoto R, Ono Y, Iwakura Y, Omata K, Kudo M, Satani N, Ota H, Seiji K, Takase K, Nakamura Y, Sasano H, Ito S. 8D.04: clinical benefits of administering super-selective segmental adrenal venous sampling and performing adrenal sparing surgery in the patients with primary aldosteronism. J Hypertens. 2015;33(suppl 1):e114. doi: /01. hjh b Ceolotto G, Antonelli G, Maiolino G, Cesari M, Rossitto G, Bisogni V, Plebani M, Rossi GP. Androstenedione and 17-α-hydroxyprogesterone are better indicators of adrenal vein sampling selectivity than cortisol. Hypertension. 2017;70: DOI: /HYPERTENSIONAHA Cesari M, Ceolotto G, Rossitto G, Maiolino G, Seccia TM, Rossi GP. The intra-procedural cortisol assay during adrenal vein sampling: Rationale and Design of a Randomized Study (I-Padua). High Blood Press Cardiovasc Prev. 2017;24: doi: /s Helber A, Wambach G, Hummerich W, Bönner G, Meurer KA, Kaufmann W. Evidence for a subgroup of essential hypertensives with non-suppressible excretion of aldosterone during sodium loading. Klin Wochenschr. 1980;58: Gouli A, Kaltsas G, Tzonou A, Markou A, Androulakis II, Ragkou D, Vamvakidis K, Zografos G, Kontogeorgos G, Chrousos GP, Piaditis G. High prevalence of autonomous aldosterone secretion among patients with essential hypertension. Eur J Clin Invest. 2011;41: doi: /j x. 20. Markou A, Pappa T, Kaltsas G, Gouli A, Mitsakis K, Tsounas P, Prevoli A, Tsiavos V, Papanastasiou L, Zografos G, Chrousos GP, Piaditis GP. Evidence of primary aldosteronism in a predominantly female cohort of normotensive individuals: a very high odds ratio for progression into arterial hypertension. J Clin Endocrinol Metab. 2013;98: doi: /jc Markou A, Sertedaki A, Kaltsas G, Androulakis II, Marakaki C, Pappa T, Gouli A, Papanastasiou L, Fountoulakis S, Zacharoulis A, Karavidas A, Ragkou D, Charmandari E, Chrousos GP, Piaditis GP. 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5 Rossi and Funder AVS, CT, and Lateralization of APA Mulatero P, Monticone S, Burrello J, Veglio F, Williams TA, Funder J. Guidelines for primary aldosteronism: uptake by primary care physicians in Europe. J Hypertens. 2016;34: doi: / HJH Satoh F, Morimoto R, Ono Y, et al. Measurement of peripheral plasma 18-oxocortisol can discriminate unilateral adenoma from bilateral diseases in patients with primary aldosteronism. Hypertension. 2015;65: doi: /HYPERTENSIONAHA Stowasser M, Bachmann AW, Tunny TJ, Gordon RD. Production of 18-oxo-cortisol in subtypes of primary aldosteronism. Clin Exp Pharmacol Physiol. 1996;23: Eisenhofer G, Dekkers T, Peitzsch M, Dietz AS, Bidlingmaier M, Treitl M, Williams TA, Bornstein SR, Haase M, Rump LC, Willenberg HS, Beuschlein F, Deinum J, Lenders JW, Reincke M. Mass spectrometry-based adrenal and peripheral venous steroid profiling for subtyping primary aldosteronism. Clin Chem. 2016;62: doi: /clinchem Response to Adrenal Vein Sampling Is the Preferred Method to Select Patients With Primary Aldosteronism for Adrenalectomy: Pro Side of the Argument Jaap Deinum, Aleksander Prejbisz, Jacques W.M. Lenders, Gert Jan van der Wilt Rossi and Funder s narrative to defend adrenal venous sampling (AVS) falls short in 3 important aspects. First, the evidence they invoke to demonstrate superiority of AVS is based on the tenet that AVS is superior to computed tomography. This leads to circular reasoning a common pitfall. In addition, most studies they refer to as evidence of superiority of AVS lack proper follow-up data to verify the diagnoses. Second, patients with primary aldosteronism deserve better than clinical practice evolved as cottage industry. Although they suggest improvements of AVS much in line with our arguments, they fail to make the final step: to design and to perform studies of better quality. Their argument that in the absence of a standardized procedure and good evidence, management relies mainly on the clinician s competence is medicine of a remote past. Without standards that are easily transferred to colleagues less versed in the intricacies of primary aldosteronism, foggy and unaccountable practice is the result. Third, regarding their critique on SPARTACUS (Subtyping Primary Aldosteronism: a Randomized Trial Comparing Adrenal Vein Sampling and Computed Tomography Scan), we agree with doubts on cosyntropin although many studies use cosyntropin, even some Rossi and Funder cite as evidence for AVS superiority. We contest their unsubstantiated statements on patient selection and medication regimen. Both are according to published guidelines; age and sex distribution are similar to the recently published PATO study (Primary Aldosteronism in Torino). This discussion shows that also proponents of AVS who are less critical of previous evidence than we are acknowledge the need for improvement of diagnosis and subtyping of primary aldosteronism. The future is to well-designed diagnostic trials. Reference 1. Monticone S, Burrello J, Tizzani D, Bertello C, Viola A, Buffolo F, Gabetti L, Mengozzi G, Williams TA, Rabbia F, Veglio F, Mulatero P. Prevalence and clinical manifestations of primary aldosteronism encountered in primary care practice. J Am Coll Cardiol. 2017;69: doi: /j. jacc